The present invention relates to methods and compositions for treating renal disorders. More specifically, the present invention relates to methods and compositions comprising standardized extract of Tinospora cordifolia in the treatment of renal disorders such as chronic recurrent urinary tract infections, both complicated and uncomplicated.
Renal disorders form important components of both "lifestyle" and "infective" diseases in humans. Both types of diseases can lead to chronic kidney damage and can progress to end stage renal disease and chronic renal failure. Complicated urinary tract infections represent the most common and important group of disorders that constitute a major cause of chronic renal failure.
An important renal disease associated with morbidity and progress to end stage renal failure is chronic recurrent urinary tract infection, which can lead to renal scarring going to chronic pyelonephritis. Chronic recurrent urinary tract infection is usually treated by therapy with antibacterial agents. However, the development of increasing antibacterial resistance with each episode plays an important role in non-healing with slow and steady progression to a chronic state due to impaired immunity produced by repeated infections.
Urinary tract infections (UTIs) are one of the most common infectious diseases encountered in the practice of medicine today. UTIs encompass a spectrum of clinical and pathological conditions involving various parts of the urinary tract. The syndromes range from symptomatic bacteriuria to peripheric abscess with sepsis. Each has its own unique epidemiology, natural history and diagnostic considerations. Differentiating syndromes associated with UTI have important implications for treatment and prognosis.
Complicated urinary tract infection refers to urinary infection, which occurs in an individual with functional metabolic or structural abnormalities of the genitourinary tract. These abnormalities promote infection through compromising adequate drainage of urine or by establishing a nidus, from which bacteria cannot be eradicated, as in case of diabetics and in renal failure subjects.
Recurrent infection may be either relapse, where infection recurs with the pre-therapy infecting organism and suggests a failure to eradicate the organism from the genitourinary tract, or re-infection, where a new organism establishes infection. In recurrent UTI the impaired host defense and the ability of the bacteria to adhere to the cell walls lining the ureters, play an important role in the recurrences.
E. coli is the cause in most of the UTI cases and treatment consists of a course of antibacterials. Other organisms involved are Klebsiella, Proteus, Enterobacter, Citrobacter, Serratia and Pseudomonas. Synthetic antimicrobial agents of the older members of quinolone class such as nalidixic acid have been available for the treatment of UTI. However, these drugs have limited therapeutic utility and the organisms rapidly develop resistance.
Newer drugs such as fluorinated 4-quinolones like ciprofloxacin, ofloxacin, norfloxacin, lomefloxacin, trimethoprim-sulfamethoxazole and other antibacterial agents like amoxicillin, nitrofurantoin and ampicillin are equally efficacious against UTI. Complicated UTIs normally require a longer course of antibacterial therapy that is associated with the various side effects.
Hence there is a need to analyze the present treatment of renal disorders and to develop new effective drug therapies that are devoid of side effects for the above renal diseases.
Tinospora cordifolia also known in India as Guduchi/ amruta is one of the Rasayanas which has been designated as "Ekadravya Rasayana" in the ancient Indian system of medicine [Ayurveda] i.e. to be used as a single entity for its pro-host immunostimulant activity and has been called "the Nectar of life". This is one of the plant products that has been extensively studied as an immunostimulant by well-known practitioners of modern allopathic medicine.
Numerous polyherbal classical and proprietary formulations having Tinospora cordifolia as one of the ingredients, are available in the Indian market as well as for export. Also, products such as ADBAC™ and IMMUMOD™ having Tinospora cordifolia as a single herb component as a natural immunostimulant are commercially available in India. These products claim to contain an aqueous extract of Tinospora cordifolia.
Extensive experimental and clinical work has shown the immune enhancing effects of Tinospora cordifolia. This has been established to be mediated through stimulation of macrophage activity which in turn leads to increased secretion of granulocyte-monocyte colony stimulating factor (GM-CSF).
Though voluminous data are available on the use of Tinospora cordifolia in various diseases, there is no indication in the published literature regarding the use of Tinospora cordifolia as an immunoadjuvant in the treatment of renal disorders such as chronic recurrent urinary tract infections; both complicated and uncomplicated.
The present invention comprises a standardized extract of Tinospora cordifolia, for use in a method for the treatment of renal disorders according to claim 1.
The above summary of the present invention is not intended to describe each discussed embodiment of the present invention. This is the purpose of the detailed description that follows.
Complicated urinary tract infections represent the most common and important group of disorders that constitute a major cause of chronic renal failure.
Urinary infection in the setting of functional or structural abnormalities of the urinary tract will not be treated effectively unless the underlying abnormality promoting the infection is corrected; it reflects that individuals with complicated UTIs tend to have recurrent infection and multiple intervention. Prior anti-bacterial therapy and the potential for nosocomial acquisition of micro-organisms both increase the likelihood of more resistant microorganisms emerging in subsequent infections.
It has been observed that recurrent infection is the norm for individuals with complicated UTIs where the underlying genitourinary abnormality cannot be corrected; or metabolic abnormality can be controlled; but cannot be cured. The symptoms of infection often subside before the bacteria causing the infection are completely eliminated, hence requiring a long-term treatment regimen.
In the case of recurrent UTIs, conventional anti-bacterial therapy means the use of anti-bacterial agents selected from trimethoprim, trimethoprim-sulfamethoxazole combination, ampicillin, cephalothin, nitrofurantoin, gentamicin and fluoroquinolones (e.g. ciprofloxacin, norfloxacin).
The present inventors have developed an immunoadjuvant therapy for the treatment of renal diseases such as chronic recurrent urinary tract infection.
In an embodiment, the present invention relates to the novel use of the standardized extract of Tinospora cordifolia as an immunoadjuvant in the treatment of renal disorders such as chronic recurrent urinary tract infections; both complicated and uncomplicated.
In another embodiment, the invention relates to method of treatment of renal disorders such as recurrent urinary tract infection occurring due to relapsing E. coli, Klebsiella, Proteus, Enterobacter, Citrobacter, Serratia and Pseudomonas infection by providing effective immunoadjuvant therapy, in conjunction to conventional antibacterial therapy.
In another embodiment, the invention provides a pharmaceutical composition comprising standardized extract of Tinospora cordifolia along with other pharmaceutical carriers.
In an embodiment, the invention provides a pharmaceutical composition comprising standardized extract of Tinospora cordifolia in combination with at least one other herbal constituent.
In another embodiment of the invention is directed to a method of making a composition useful for treating renal disorders such as chronic recurrent urinary tract infections by mixing the Tinospora cordifolia extract with a carrier or diluent.
While not intending to be bound by theory, the immune enhancing effects of Tinospora cordifolia are believed to be mediated through stimulation of macrophage activity leading to increased secretion of granulocyte - monocyte colony stimulating factor [GM-CSF]. As a result, increases in IL2 and IFN-gamma result in increased natural killer cell activity, ultimately leading to an anti-inflammatory effect.
Tinospora cordifolia can be obtained commercially. By way of example, Tinospora cordifolia can be obtained commercially from Kisalaya Herbals Limited, Indore, India. Tinospora cordifolia extract can also be prepared. By way of example, one process for the preparation of an extract of Tinospora cordifolia comprises the following steps: 1) powdering dried stems of Tinospora cordifolia followed by treating it with water, 2) extracting it with hot water, 3) filtering the extract obtained in step 2, 4) partly concentrating the filtrate under vacuum, and 5) spray drying the material obtained in step 4 to get the extract as fine powder.
Tinospora cordifolia extract can be standardized by the technique of phagocytosis measurement using polymorphonuclear leukocytes (PMNL) that evaluates the immunomodulatory potential of the extract (
The composition comprising standardized extract of Tinospora cordifolia can be mixed with pharmaceutically acceptable carriers and formulated into therapeutic dosage forms such as tablets, capsules, liquid orals, nasal sprays, creams, sterile injectable preparations, suppositories, etc. The composition can be administered by known techniques, such as orally, parentally (including subcutaneous injection, intravenous, intramuscular, intrasternal or infusion techniques), by inhalation spray, topically, by absorption through a mucous membrane, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, or vehicles. The extract of Tinospora cordifolia, as it is in the composition, may be a liquid, a powder, etc.
As used herein, the term pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium laryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents; preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
The composition of the invention may be prepared by mixing the various components of the composition using conventional methods. The preferred composition of the invention may be prepared according to the constituent ranges set forth herein in Table 2.
In an embodiment, the dose of the standardized extract varies between 20-80 mg/kg body wt per day. In a particular embodiment, the dose varies between 20 - 25 mg/kg body wt. administered in equal portions twice a day or thrice a day. In a further embodiment, in children, the dose varies between 25 - 30 mg/kg body wt. administered in equal portions twice a day or thrice a day. In an embodiment, total dose of the standardized extract varies between 400mg-4000mg per day.
In an embodiment, the standardized extract is administered to patients suffering from UTI for a period of one month to 3 months continuously, and intermittently up to 18 months.
The period of administration of the standardized extract may vary depending on intensity of disease and response of the patient.
In an exemplary embodiment, a composition of standardized extract of Tinospora cordifolia extract was prepared in the form of a capsule to study the effect of the herbal extract of Tinospora cordifolia as an immunoadjuvant in patients in the treatment of chronic recurrent urinary tract infection.
During clinical studies it has been observed that, in a group of patients with chronic UTI under the treatment of anti bacterial like Lomefloxacin. Trimethoprim, Sulphamethoxazole, Ciprofloxacin and the like, the colony count in urine culture was more than about 105. After the treatment with the pharmaceutical composition comprising Tinospora cordifolia there is either no growth, or count in urine culture is less than about 103.
This indicates that the treatment of cases having recurrent urinary tract infection with proven episodes on more than about 20 occasions over a period of more than about 15 months, with a pharmaceutical composition comprising herbal extract of Tinospora cordifolia stops any further episode of urinary tract infection and urine culture may become negative in the future. This indicates that a pharmaceutical composition comprising standardized extract of Tinospora cordifolia may act on the root cause of the relapse of urinary tract infection by eliminating the organism from the system.
The following examples are merely intended to illustrate the present invention in further detail but should by no means be construed as limiting the scope of the invention.
The Tinospora cordifolia extract was obtained from Kisalaya Herbals Limited, Indore, India. The extract was a brown colored, free flowing fine powder which was bitter in taste. The extract was characterized by analytical tests such as Bulk density (tapped), pH , alcohol soluble extractives and water soluble extractives. The results obtained were: bulk density (tapped): 0.55 - 0.65/ml; pH. (1% w/v in Water): 5-6.8; alcohol soluble extractives: 8-15% w/w on dried basis; and water soluble extractives: not less than 95% w/w on dried basis.
Human blood (2-3 drops) was collected on a sterilized glass slide. The slide was kept on the cotton bed in the sterilized petri-dish. It was then incubated at 37°C for 25 minutes, the clot was removed and the slide was washed with saline (0.9% aq. NaCl solution). The presence of PMNLs (polymorphonuclear leukocytes) was confirmed by observing the slide under a microscope. PMNLs were then incubated with different concentrations of the Tinospora cordifolia extract or a control at 37° C for 35-40 min.
After 40 minutes the slide was drained, then flooded with culture of Candida albicans and incubated at 37°C for 1 h.
The slide was then washed with water, fixed with methanol, stained with a Giemsa stain and observed under an oil immersion microscope. The mean number of phagocytosed cells on the slide was determined for 100 granulocytes using morphological criteria.
Percentage phagocytosis was calculated for both control and Tinospora cordifolia and is shown in Table 1 below:
Percentage phagocytosis values are indicative of the activity level of the immune system. A greater percentage phagocytosis demonstrates enhanced activity of the immune system. Therefore, the data indicates that Tinospora cordifolia activates the immune system more than the control.
A standardized extract of Tinospora cordifolia was combined with colloidal silicon dioxide and magnesium stearate to form a composition with the amounts listed below in Table 2. The composition was then made into the form of a capsule.
The Tinospora cordifolia composition of Example 2 was administered orally to patients with recurrent urinary tract infection. Patients were divided into 2 groups. Group I consisted of patients, young males, and females who continued to have recurrent infections over a period of three months in spite of adequate anti-bacterial therapy and in whom no underlying cause, such as anatomical or physiological [e.g., pregnancy related] aberrations, was found. Group II consisted of patients of middle and older age groups who had chronic recurrent urinary tract infection that continued beyond 3 months and up to 18 months, in spite of the fact that remediable causes like obstruction or underlying G.U. Tuberculosis had long been corrected.
The Group I subjects consisted of 4 patients who received the Tinospora cordifolia composition in the dosage of 20 - 25 mg/kg body wt. for one month, about 10 days before and 20 days after starting appropriate anti-bacterial agent such as Lomefloxacin, Trimethoprim, Sulphamethoxazole, and Ciprofloxacin. Duration of administration of Tinospora cordifolia may be reduced to 20 - 24 days depending on urine -routine, culture, and anti-bacterial sensitivity test results.
The subjects in Group II were administered the Tinospora cordifolia composition in the same dosage; but given for longer period of time of 3 months. One patient from Group II was given 2 courses of Tinospora cordifolia spread over a nine-month period. He had recurrent UTI with proven episodes based on urine culture on 21 occasions over a period of 18 months before administering Tinospora cordifolia.
Colony count from urine culture was calculated before and after the administration of Tinospora cordifolia. The results are shown in Table 3 below.
In addition, all treated patients had a complete resolution over a one year observation period with no further episodes of UTI and urine culture becoming negative and remaining so over the period of observation.
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.